Preparation of extended shelf-life biodegradable, biocompatible microparticles containing a biologically active agent

A method for preparing biodegradable, biocompatible microparticles. A first phase is prepared that includes a biodegradable, biocompatible polymeric encapsulating binder, and an active agent having limited water solubility dissolved or dispersed in a solvent. An aqueous second phase is prepared. The first and second phases are combined to form an emulsion in which the first phase is discontinuous and the second phase is continuous. The two phases are separated. The discontinuous first phase is washed with water, or an aqueous solution of water and a solvent for residual solvent in the first phase, to reduce the level of residual solvent in the microparticles to less than about 2% by weight of the microparticles. Also disclosed are a microencapsulated drug prepared by the method for preparing biodegradable, biocompatible microparticles, and a pharmaceutical composition that includes biodegradable and biocompatible microparticles in a pharmaceutically acceptable carrier.

Skip to:  ·  Claims  ·  References Cited  · Patent History  ·  Patent History

Claims

1. A method for preparing biodegradable, biocompatible microparticles comprising:

A) preparing a first phase comprising:
(1) a biodegradable, biocompatible polymeric encapsulating binder, and
(2) an active agent having limited water solubility, dissolved or dispersed in a first solvent;
B) preparing an aqueous second phase;
C) combining said first phase and said second phase under the influence of mixing means to form an emulsion in which said first phase is discontinuous and said second phase is continuous;
D) separating said discontinuous first phase from said continuous second phase; and
E) washing said discontinuous first phase with
(1) water at a temperature in the range of from about 25.degree. C. to about 40.degree. C., or
(2) an aqueous solution comprising water and a second solvent for residual first solvent in said first phase,
thereby reducing the level of residual first solvent to less than about 2% by weight of said microparticles.

2. The method of claim 1 further comprising a step of quenching between step C) and step D).

3. The method of claim 1 where in said biodegradable, biocompatible polymeric encapsulating binder is selected from the group consisting of poly(glycolic acid), poly(d,l-lactic acid), poly(l-lactic acid), and copolymers of the foregoing.

4. The method of claim 1, wherein said first solvent is a solvent blend of at least two mutually miscible organic solvents.

5. The method of claim 4 wherein one of said organic solvents is an ester.

6. The method of claim 5 wherein said ester is of the structure R.sup.1 COOR.sup.2 wherein R.sup.1 and R.sup.2 are independently selected from the group consisting of alkyl moieties of from 1 to 4 carbon atoms.

7. The method of claim 6 wherein said ester is ethyl acetate.

8. The method of claim 4 wherein one of said organic solvents is benzyl alcohol.

9. The method of claim 4 wherein said solvent blend comprises ethyl acetate and benzyl alcohol.

10. The method of claim 1 wherein said second phase comprises a hydrophilic colloid.

11. The method of claim 10 wherein said hydrophilic colloid is poly(vinyl alcohol).

12. The method of claim 1 wherein said mixing means comprises a static mixer.

13. The method of claim 1 wherein said active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.

14. The method of claim 1 wherein said aqueous solution comprises water and a C.sub.1 -C.sub.4 alcohol.

15. The method of claim 14 wherein said C.sub.1 -C.sub.4 alcohol is ethanol.

16. A method for preparing biodegradable, biocompatible microparticles comprising:

A) preparing a first phase comprising
1) a biodegradable, biocompatible polymeric encapsulating binder selected from the group consisting of poly(glycolic acid), poly(d,l-lactic acid), poly(l-lactic acid), and copolymers of the foregoing, and
2) an active agent selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof dissolved or dispersed in a blend comprising ethyl acetate and benzyl alcohol, said blend being free from halogenated hydrocarbons;
B) preparing a second phase comprising polyvinyl alcohol dissolved in water;
C) combining said first phase and said second phase in a static mixer to form an emulsion in which said first phase is discontinuous and said second phase is continuous;
D) immersing said first and said second phases in a quench liquid;
E) isolating said discontinuous first phase in the form of microparticles; and
F) washing said discontinuous first phase with an aqueous solution comprising water and ethanol, thereby reducing the level of benzyl alcohol to less than about 2% by weight of said microparticles.

17. A microencapsulated drug prepared by a method for preparing biodegradable, biocompatible microparticles comprising:

A) preparing a first phase comprising:
(1) a biodegradable, biocompatible polymeric encapsulating binder, and
(2) an active agent having limited water solubility, dissolved or dispersed in a first solvent;
B) preparing an aqueous second phase;
C) combining said first phase and said second phase under the influence of mixing means to form an emulsion in which said first phase is discontinuous and said second phase is continuous;
D) separating said discontinuous first phase from said continuous second phase; and
E) washing said discontinuous first phase with
(1) water at a temperature in the range of from about 25.degree. C. to about 40.degree. C., or
(2) an aqueous solution comprising water and a second solvent for residual first solvent in said first phase,
thereby reducing the level of residual first solvent to less than about 2% by weight of said microparticles.

18. The microencapsulated drug of claim 17 wherein the process further comprises a step of quenching between step C) and step D).

19. The microencapsulated drug of claim 17, wherein said first solvent is a solvent blend of at least two mutually miscible organic solvents.

20. Microencapsulated risperidone, 9-hydroxyrisperidone, or pharmaceutically acceptable salts thereof prepared by a process comprising:

A) preparing a first phase comprising:
1) a biodegradable, biocompatible polymeric encapsulating binder selected from the group consisting of poly(glycolic acid), poly(d,l-lactic acid), poly(l-lactic acid), and copolymers of the foregoing, and
2) an active agent selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof, dissolved or dispersed in a blend comprising ethyl acetate and benzyl alcohol, said blend being free from halogenated hydrocarbons;
B) preparing a second phase comprising polyvinyl alcohol dissolved in water;
C) combining said first phase and said second phase in a static mixer to form an emulsion in which said first phase is discontinuous and said second phase is continuous;
D) immersing said first and second phases in a quench liquid;
E) isolating said discontinuous first phase in the form of microparticles; and
F) washing said discontinuous first phase with an aqueous solution comprising water and ethanol, thereby reducing the level of benzyl alcohol to less than about 2% by weight of said microparticles.

21. A pharmaceutical composition comprising biodegradable and biocompatible microparticles in a pharmaceutically acceptable carrier, said microparticles comprising:

a polymeric encapsulating binder having dispersed or dissolved therein an active agent, and
less than about 2% by weight residual solvent, wherein said residual solvent is residual derived from a solvent employed in the preparation of said microparticles.

22. The composition of claim 21 wherein said polymeric encapsulating binder comprises a polymeric matrix material selected from the group consisting of poly(glycolic acid), poly(d,l-lactic acid), poly(l-lactic acid), and copolymers of the foregoing.

23. The composition of claim 22 wherein said polymeric matrix material is a copolymer of poly(glycolic acid) and poly(d,l-lactic acid).

24. The composition of claim 23 wherein the content of said residual solvent is in the range of from about 0.5 to about 1.5% by weight.

25. The composition of claim 24 wherein said residual solvent is benzyl alcohol.

26. The composition of claim 25 wherein the molar ratio of lactide to glycolide is in the range of 85:15 to 50:50.

27. The composition of claim 25 wherein the microparticles comprise from about 1 to about 90 wt. % of said active agent.

28. The composition of claim 25 wherein the microparticles comprise from about 35 to about 40 wt. % of said active agent.

29. The composition of claim 25 wherein the microparticles range in size from about 1 to about 500 microns.

30. The composition of claim 25 wherein the microparticles range in size from about 25 to about 180 microns.

31. The composition of claim 25 wherein said active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.

32. A pharmaceutical composition comprising biodegradable and biocompatible microparticles, ranging in size from about 25 to about 180 microns, in a pharmaceutically acceptable carrier, said microparticles comprising:

a copolymer of poly(glycolic acid) and poly(d,l-lactic acid) wherein the molar ratio of lactide to glycolide is in the range of from about 85:15 to about 50:50 and having dispersed or dissolved therein from about 35 to about 40% of an active agent comprising risperidone, 9-hydroxy-risperidone, or pharmaceutically acceptable salts thereof, and
from about 0.5 to about 1.5% by weight of benzyl alcohol.

33. The method of claim 1, wherein said active agent comprises at least one basic moiety.

34. The microencapsulated drug of claim 17, wherein said active agent comprises at least one basic moiety.

35. The composition of claim 21, wherein said active agent comprises at least one basic moiety.

36. The composition of claim 25, wherein said active agent comprises at least one basic moiety.

37. A method of preparing biodegradable, biocompatible microparticles, comprising:

A) preparing a first phase, said first phase comprising an active agent, a biodegradable, biocompatible polymer, and a first solvent;
B) preparing a second phase, wherein said first phase is substantially immiscible in said second phase;
C) flowing said first phase through a static mixer at a first flow rate;
D) flowing said second phase through said static mixer at a second flow rate so that said first phase and said second phase flow simultaneously through said static mixer thereby forming microparticles containing said active agent;
E) isolating said microparticles; and
F) washing said microparticles with water at an elevated temperature or with an aqueous solution comprising water and a second solvent for residual first solvent in said microparticles, thereby reducing the level of residual first solvent to less than about 2% by weight of said microparticles.

38. The method of claim 37, wherein said first solvent comprises ethyl acetate and benzyl alcohol.

39. The method of claim 38, wherein said active agent comprises at least one basic moiety.

40. The method of claim 1, wherein said second phase comprises an aqueous solution of a hydrophilic colloid.

41. The method of claim 1, wherein said second phase comprises an aqueous solution of a surfactant.

42. The method of claim 1, wherein said second phase is water.

43. The microencapsulated drug of claim 17, wherein said second phase comprises an aqueous solution of a hydrophilic colloid.

44. The microencapsulated drug of claim 17, wherein said second phase comprises an aqueous solution of a surfactant.

45. The microencapsulated drug of claim 17, wherein said second phase is water.

46. The method of claim 1, wherein said first solvent is free from halogenated hydrocarbons.

47. The microencapsulated drug of claim 17, wherein said first solvent is free from halogenated hydrocarbons.

48. The method of claim 37, wherein said first solvent is free from halogenated hydrocarbons.

49. A method for preparing biodegradable, biocompatible microparticles, comprising:

A) contacting microparticles comprising a biodegradable, biocompatible polymer matrix containing an active agent and an organic solvent with an aqueous washing system to thereby reduce the level of residual organic solvent to less than about 2% by weight of said microparticles, wherein said aqueous washing system is (1) at a temperature in the range of from about 25.degree. C. to about 40.degree. C. for at least part of step A, or (2) an aqueous solution comprising water and a water-miscible solvent for said organic solvent; and
B) recovering said microparticles from said aqueous washing system.

50. The method of claim 49, wherein said active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.

51. The method of claim 49, wherein said organic solvent is a solvent blend of at least two mutually miscible organic solvents.

52. The method of claim 51, wherein said solvent blend comprises ethyl acetate and benzyl alcohol.

Referenced Cited
U.S. Patent Documents
3523906 August 1970 Vrancken et al.
3691090 September 1972 Kitajima et al.
3737337 June 1973 Schnoring et al.
3773919 November 1973 Boswell et al.
3891570 June 1975 Fukushima et al.
3960757 June 1, 1976 Morishita et al.
4221862 September 9, 1980 Naito et al.
4384975 May 24, 1983 Fong
4389330 June 21, 1983 Tice et al.
4530840 July 23, 1985 Tice et al.
4940588 July 10, 1990 Sparks et al.
5066436 November 19, 1991 Komen et al.
5407609 April 18, 1995 Tice et al.
5478564 December 26, 1995 Wantier et al.
5541172 July 30, 1996 Labrie et al.
5688801 November 18, 1997 Mesens et al.
Foreign Patent Documents
0 486 959 A1 May 1992 EPX
WO 89/03678 May 1989 WOX
WO 90/13361 November 1990 WOX
WO 94/10982 May 1994 WOX
WO 95/13799 May 1995 WOX
Other references
  • Koch Engineering Co., Inc., Static Mixing Technology advertisement, pp. 1-15. Baker, J.R., "Motionless Mixers Stir Up New Uses", Chemical Engineering Progress, pp. 32-38, (Jun. 1991). Mutsakis, M., et al., "Advances in Static Mixing Technology", Chemical Engineering Progress, pp. 42-48, (Jul. 1986). Bodmeier, R., et al., International Journal of Pharmaceutics, 43:179-186 (1988). Beck, L.R., et al., Biology of Reproduction, 28:186-195 (Feb. 1983). Toyomi Sato et al., Pharmaceutical Research, 5:21-30 (1988). Wen-I Li et al., Journal of Controlled Release, 37:199-214 (Dec. 1995). H.V. Maulding et al., Journal of Controlled Release, 3:103-117 (Mar. 1986). Hongkee Sah et al., Pharmaceutical Research, 13:360-367 (Mar. 1996). R. Jalil et al., Journal of Microencapsulation, vol. 7, No. 3, Jul.-Sep. 1990, pp. 297-319.
Patent History
Patent number: 5792477
Type: Grant
Filed: May 2, 1997
Date of Patent: Aug 11, 1998
Assignees: Alkermes Controlled Therapeutics, Inc. II (Cambridge, MA), Janssen Pharmaceutica
Inventors: Michael E. Rickey (Loveland, OH), J. Michael Ramstack (Lebanon, OH), Danny H. Lewis (Hartselle, AL), Jean Mesens (Wechelderzande)
Primary Examiner: Carlos Azpuru
Attorney: Andrea G. Howrey & Simon Reister
Application Number: 8/850,679
Classifications
Current U.S. Class: Contains Solid Synthetic Resin (424/501); Pore Forming In Situ (e.g., Foaming, Etc.) (264/41); 428/40221
International Classification: A61K 950; B01J 1302; B32B 516;